Airless mixing with a by-pass syringe

ABSTRACT

A method for transferring and mixing a pharmaceutical mixture utilizing a by-pass cartridge and a syringe. After mixing the dry component and the diluent in the by-pass cartridge, the mixture can be passed to a syringe which includes a syringe plunger having a fluid passageway therein with a hydrophobic membrane covering the passageway. The mixture can be transferred back and forth between the by-pass cartridge and the syringe through a small bore to achieve mixing, particularly in the case of microspheres held in suspension.

This application is a Continuation-in-Part of application Ser. No.12/462,696 filed Aug. 6, 2009.

FIELD OF THE INVENTION

The present invention relates to improvements in syringes and inparticular, relates to an improved syringe wherein two or moresubstances are mixed and also to a method for the mixing of two or moresubstances in a syringe.

BACKGROUND OF THE INVENTION

In pharmaceutical delivery systems, it is often required that a drug inpowder form be mixed with a diluent in order to be able to deliver thedrug to a patient. To date, this is frequently done by injecting thediluent into a vial containing the powder drug, mixing the drug with thediluent and then aspirating the drug in fluid form into a syringe forsubsequent injection into the patient. A manual mixing such as this canbe cumbersome and inconvenient and can also lead to wastage of some ofthe drug which may remain in the vial.

Other more automated systems for mixing the drug and diluent have beendeveloped and are shown in U.S. Pat. Nos. 5,817,055 and 5,716,338. Inthese patents, the mixing of the drug and diluent is achieved in what isknown as a by-pass syringe having two compartments; one containing thedrug and the other the diluent.

These devices have been used for many years to aseptically packagelyophilized or “freeze-dried” medications together with their diluents.In recent years specially coated drug micro-units have been produced inthe form of microspheres which release slowly into the bloodstream whenadministered are also now being packaged in these devices. The packagingof lyophilized drugs requires that the liquid drug admixture be filledinto the top chamber so that once frozen, all water will sublimate undervacuum leaving a dried cake of residual drug product. For this reason anaqueous diluent needs to be filled in the lower chamber of the syringeafter the freeze drying cycle. The production of powdered products suchas microspheres requires that the diluent be filled in the lower chamberfirst followed by powder filling in the upper chamber. This will ensurethat the diluent is well sealed before entering the well isolatedpowder-filling environment where unwanted powder contamination is aconcern.

The preparation for administration in these double chamber by-passsyringes however is much the same and requires that the device always beheld vertically with the exit nozzle pointing upwards. The mixing actionoccurs when the rear plunger is pushed forward very slowly. Thismovement can be dampened by using a threaded plunger rod so that theuser must screw the rod thereby providing a slow controlled upwardmovement of the rear plunger. This movement moves the entire diluentincluding the upper plunger upwards into the by-pass area (any fastuncontrolled movement would move the plunger beyond the by-pass area andblock flow of the diluent). Continued slow upward movement will causeall of the diluent to flow through the by-pass around the upper plungerand into the upper chamber mixing with drug component and expelling someof the air above it.

At this point the user must stop pressure on the plunger rod and beginswirling or shaking the syringe to ensure dissolution or suspension ofthe drug. If either component of the admixture contains a surface activeagent to promote wetting then excessive foaming can be a problem as wellas the problem of entrained air bubbles. After some time and when theadmixture is suitably mixed, and foam or bubbles have been allowed todissipate, then the user can slowly push the plunger rod to expel theair above the drug surface, attach a needle and inject the medication.

Quite apart from the above, there may also be a requirement to remix amixture which has separated out and needs to be transferred to a syringetype structure.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a by-pass typesyringe which has a venting structure to permit the expelling of airtherefrom.

It is a further object of the present invention to provide a syringewherein mixing is accomplished by passing the components back and forththrough a relatively small opening to subject the mixture to a shearingaction.

It is a further object of the present invention to provide a method formixing two substances in a syringe structure.

According to one aspect of the present invention, there is provided atransfer and mixing device comprising an outer housing, a by-passcartridge having a by-pass formed therein, the by-pass cartridge beingmounted within the outer housing, a septum located at a front end of theby-pass cartridge, a first plunger located at a rear end of the by-passcartridge, a second plunger located intermediate the septum and thefirst plunger, the second plunger being located rearwardly of theby-pass, a syringe socket at a front end of the outer housing, thesyringe socket including a piercing member extending inwardly towardsthe septum, a syringe securable to the syringe socket, a syringe plungermounted in the syringe, the syringe plunger having a fluid passagewaytherein, a hydrophobic membrane covering the passageway, the passagewaythereby permitting the passage of gas therethrough, and a plunger rod.

According to a further aspect of the invention, there is provided amethod of mixing a pharmaceutical mixture contained within a container,the container having a plunger located proximate a rear end thereof anda fluid outlet located at a front end thereof, the method comprising thesteps of providing a syringe, the syringe having a syringe plunger, afluid passageway extending through the plunger, and a hydrophobicmembrane extending across the fluid passageway, pushing the plunger ofthe container to cause the mixture therein to pass through a borecommunicating with the syringe plunger such that air is expelled throughthe hydrophobic membrane, and the mixture passes into the syringe, andsubsequently pushing the syringe plunger such that the mixture passesback through the bore extending between the fluid passageway and thecontainer, the bore being sized to provide a mixing action to thepharmaceutical mixture passing therethrough.

According to a still further aspect of the invention, there is provideda method of transferring and mixing a pharmaceutical mixture, the methodcomprising the steps of supplying a first device comprising an outerhousing, a by-pass cartridge having a by-pass formed therein, theby-pass cartridge being mounted within the outer housing, a septumlocated at a front end of the by-pass cartridge, a first plunger locatedat a rear end of the by-pass cartridge, a second plunger locatedintermediate the septum and the first plunger, the second plunger beinglocated rearwardly of the by-pass, a syringe socket at a front end ofthe outer housing, the syringe socket including a piercing memberextending inwardly towards the septum, a first compartment having apharmaceutical substance therein being defined between the septum andthe second plunger, a second compartment having a diluent therein beingdefined between the first and second plungers, securing a syringe to thesyringe socket, the syringe having a syringe plunger mounted therein,the syringe plunger having a fluid passageway therein, a hydrophobicmembrane covering the passage, the hydrophobic membrane permitting thepassage of gas therethrough, securing a plunger rod to the first plungerat the rear end of the by-pass cartridge, advancing the first plunger tothereby cause the second plunger to move to the by-pass and permit thediluent in the second compartment to mix with the substance in the firstcompartment to thereby form a mixture, exerting a continued pressure onthe plunger rod to cause air to advance from the first compartment tothe syringe and through the hydrophobic membrane, exerting a continuingpressure on the plunger rod such that the mixture from the firstcompartment passes through the piercing member into the syringe, andusing a plunger to move the syringe plunger to retransfer the mixtureinto the first compartment of the by-pass cartridge.

As used herein, the term “container” includes any type of vessel havinga cavity therein designed to receive one or more substances. Generally,the container will have an inlet/outlet at opposed ends thereof. Theword container will thus include, in the preferred embodiments, varioustypes of syringes and/or cartridges.

Also, as used herein, the term “mixture” will refer to the combinationof two or more ingredients, the combination being in the form of amixture, suspension, admixture, solution, emulsification, etc. In thepreferred embodiments, the mixture of the present invention will be asuspension of microspheres and a diluent.

The by-pass cartridge referred to above may be any suitable type ofby-pass cartridge which is well-known in the art. Thus, various types ofby-pass cartridges have been employed including those having multipleby-passes.

A device for transferring a diluent to a dry pharmaceutical component bymeans of a by-pass cartridge is well known. Generally, the device willinclude plungers which form two different storage compartments. Acentrally located plunger usually divides the dry pharmaceuticalcomponent in the front of the by-pass cartridge and a diluent or liquidcomponent in the rear compartment. A pressure is exerted on a plunger(typically by attachment of a plunger rod thereto) and the rearwardplunger is advanced forwardly which will cause pressure to be exerted onthe centrally located plunger which will then advance to the locationwhere the diluent can transfer to the front compartment for mixing withthe dry pharmaceutical component.

One problem which can arise is that the rear plunger is advanced toorapidly such that it will “overshoot” the by-pass formed in thecartridge and thus render it impossible for the diluent to reach thefront compartment. It has been proposed in the art to use ascrewthreaded motion to slow down the advancement to overcome thisproblem.

In one aspect of the present invention, there is provided a rack andpinion arrangement which will also achieve a greater control overadvancement of the plungers. This arrangement, as will be discussed ingreater detail hereinbelow, permits the operator to exert a slow evenforce on the plungers such that the centrally located plunger willadvance to the by-pass area in a controlled fashion.

In one aspect of the present invention, there is provided an activationcap which permits the by-pass cartridge to be advanced such that it willbe pierced by a piercing member located at the front end of the outerhousing. This piercing member will include a bore extending therethroughsuch that a fluid passageway extends from interiorly of the by-passcartridge through the syringe.

The syringe which is securable to the syringe socket may do so by meansof a luer fitting which is well-known in the art. The syringe includes aplunger therein with the plunger preferably located at the front end ofthe syringe. The plunger is characterized by having a fluid passagewaytherethrough, with the fluid passageway having a hydrophobic membranetherein. The hydrophobic membrane may be formed of any suitable materialsuch as a polytetrafluoroethylene (PTFE) or Tyvec or similar materialssuch as PFA, PFEP, PVDA, polysulfone, nylon, etc. Such hydrophobicmembranes permit the passage of air therethrough while it has been foundthat even with moderate pressure on the hydrophobic material, liquidwill not pass therethrough while the air within the compartment isexpelled.

Thus, there is provided a mixing wherein frothing or the entrainment ofair bubbles within the liquid is prevented.

Naturally, it will be understood that other venting structures may beemployed if so desired. Thus, one could provide a venting structure onone of the walls defining the mixing compartment.

Preferably, the syringe plunger will not have means for acceptingattachment to a plunger rod, though the plunger rod will be utilized.This will prevent any reverse pressure or aspiration which would permitthe entry of air into the mixing compartments.

According to the method of one embodiment of the present invention, thefirst plunger located at the rear end of the by-pass cartridge has aplunger rod attached thereto. Subsequently, the diluent from the rearcompartment is advanced through the by-pass to the front compartmentwhere the two components are mixed together. Air will still occupy theupper portion of the first compartment.

Subsequently, the mixture is transferred through the piercing memberinto the syringe. Continued advancement of the plungers in the by-passcartridge will cause the mixture to advance into the syringe. Air abovethe mixture will be expelled through the hydrophobic membrane. As aresult, an airless mixture is achieved.

Subsequently, the mixture now free of air can be transferred back intothe front compartment of the by-pass cartridge and the mixture willundergo a “shearing” action when passing through the passageway withinthe piercing member. This continued transfer from the by-pass cartridgeto the syringe can be continued until the desired homogeneity of themixture or suspension is achieved.

The shearing action is only accomplished due to the narrow opening inthe piercing member. Preferably, the opening or internal diameter of thepiercing member is less than fifty thou (mil). Even more preferably, theinternal diameter is preferably less than 42 thou and even morepreferably, is equal to or less than 21 thou.

BRIEF DESCRIPTION OF THE DRAWINGS

Having thus generally described the invention, reference will be made tothe accompanying drawings, in which:

FIG. 1 is a cross-sectional view of the transfer and mixing assemblyaccording to one embodiment of the present invention;

FIG. 2 is an exploded view thereof;

FIGS. 3A to 3C show different configurations, in cross-sections, ofplungers having a hydrophobic membrane;

FIG. 4 is a cross-sectional view of a further embodiment of the presentinvention;

FIG. 5 is a cross-sectional view illustrating a still further embodimentof the assembly of the present invention;

FIG. 6 is a cross-sectional view illustrating a still further embodimentof the transfer and mixing assembly; and

FIG. 7 is a sectional view of a front cap having a breathable portionthereon.

DETAILED DESCRIPTION OF THE INVENTION

Referring to the drawings in greater detail and by reference charactersthereto, there is illustrated a mixing and transfer assembly generallydesignated by reference numeral 10.

Transfer and mixing assembly 10 includes a by-pass cartridge generallydesignated by reference numeral 12, an outer housing about by-passcartridge 12 and generally designated by reference numeral 14, anactivation cap 16, a plunger rod 18, a syringe 20 and a syringe plungerrod 22.

By-pass cartridge 12 has an outer wall 26 with a by-pass 28 formedtherein as is known in the art. A septum 30 covers the outlet of by-passcartridge 12 and a cap 32 extends thereover.

Mounted within by-pass cartridge 12 is a rear plunger 34 which has afemale luer fitting 36. An intermediate or middle plunger 38 is situatedrearwardly of by-pass 28. There is thus formed a rear compartment 40which is defined as the space between wall 26, rear plunger 34 andintermediate plunger 38. A front compartment 42 is defined by wall 26,intermediate plunger 38 and septum 30. For most uses, rear compartment40 will contain the diluent while a front compartment 42 will containthe dry and active pharmaceutical Component.

Plunger rod 18 includes a head 46 for ease in pushing on shaft 48. Shaft48 is provided with a male luer fitting 50 designed to engage with luerfitting 36 on rear plunger 34.

Outer housing 54 surrounds and supports by-pass cartridge 12 andincludes a side wall 54 and a top wall 56. A piercing member 58 has abore 60 extending therethrough while an upper luer female fitting 62 isprovided.

Syringe 20 includes a conventional syringe body 66 having a flange 68 atthe end thereof. Syringe body 66 is provided with a luer fitting 70designed to engage luer fitting 62 in outer housing 14. Mountedinteriorly of syringe body 66 is a plunger 72 which has a passageway 74extending therethrough. A hydrophobic membrane 76 covers passageway 74.

Syringe plunger rod 22 includes a shaft 80 having a head 82 at one endthereof and a base 84. In operation, activation cap 16 is used to pushby-pass cartridge 12 forwardly such that septum 30 is pierced therebyand a fluid passageway between syringe 20 and front compartment 42 isestablished.

Subsequently, plunger rod 18 is attached to rear plunger 34 and pressureexerted thereon. The liquid in rear compartment 40 is substantiallyincompressible and accordingly, pressure is exerted on intermediateplunger 38 to move it forwardly to the area of by-pass 28. At thispoint, the diluent can enter into front compartment 42 to mix with thepharmaceutical component therein. A continued advancement by pressure onplunger rod 18 will cause both plungers 34, 38 to advance and aircontained within front compartment 42 will pass through bore 60 ofpiercing member 58. The air will enter syringe body 66 and be expelledthrough passageway 74. In the meantime, hydrophobic membrane 76 willprevent passage of any liquid therethrough.

The continued advancement of plungers 34, 38 will force the mixture intosyringe body 66 with plunger 72 being forced rearwardly. Once all themixture has been moved to syringe body 66, plunger rod 22 may then beactivated to cause the mixture to move into front compartment 42. Thisback and forth movement may be continued as long as needed to ensure theproper mixing of the components. The passing through bore 60 which isrelatively small will ensure the mixing of the two components whilepreventing any foaming or air bubbles.

Preferably, plunger rod 22 is not secured to plunger 72. This willprevent any aspiration movement which would permit air to enter themixture.

As shown in FIGS. 3A, 3B and 3C, plunger 72 may take several differentforms. Thus, plunger 72 may have an insert 90 about which resilientmaterial 92 extends. Hydrophobic membrane 94 extends across the topthereof.

In the embodiment of FIG. 2B, hydrophobic membrane 94 merely extendsacross resilient material 92. In the embodiment of FIG. 2C, hydrophobicmembrane 94 is sandwiched between two portions of resilient material 92.

Turning to the embodiment of FIG. 4, there is illustrated a mixing andtransferring device similar to that illustrated in FIG. 1 and similarreference numerals in the 100's are employed for similar components.

In this embodiment, plunger rod 118 has a shaft 148 with threads 115formed on a portion thereof. Threads 115 engage with flange 127 formedon activation cap 116.

This arrangement permits a relatively slow movement of the plungers asthe initial movement is dependent on the turning of plunger rod 118.After threads 115 have finished, a final pushing motion may be employedas in the previously described embodiment.

In the embodiment of FIG. 5, reference numerals in the 200's areutilized for similar components.

Transfer and mixing device 210 includes a plunger rod 248 which has aplurality of teeth 229 formed on one side thereof.

A housing 231 is secured to activation cap 216. Housing 231 includes arotatable pinion 233 by means of a thumb wheel 235. Thus, movement ofthumb wheel 235 will drive plunger rod 218 in a manner previouslydescribed.

A cap 237 is mounted about plunger rod 218 and may be removed for afinal pushing action thereon.

Also, as will be noted in this drawing, syringe 220 has a coil spring239 mounted therein. A cap 241 is used for covering the end of syringebody 266.

With the arrangement of FIG. 5, transfer of the mixture into syringe 220will continue as long as pressure is exerted on plunger rod 218. Oncepressure has been removed, spring 239 will bias plunger 272 and themixture will automatically be returned to front compartment 242.

In FIG. 6, reference numerals in the 300's are employed with similarreference numerals designating similar components. The plunger rod 318,in this embodiment, includes a plurality of teeth 343 on the end ofshaft 348 proximate head 346. In this arrangement, cap 337 must beremoved and plunger rod 318 rotated such that teeth 343 will then engagepinion 333.

In FIG. 7, there is illustrated a front cap which could be employed withthe outer housing of the previous embodiments. Cap 351 includes ahydrophobic membrane 353 extending over an internal passageway with amale luer connection 355.

It will be understood that the above described embodiments are forpurposes of illustration only and that changes and modifications may bemade thereto without departing from the spirit and scope of theinvention.

1. A method of transferring and mixing a pharmaceutical mixture, themethod comprising the steps of: supplying a first device comprising anouter housing, a by-pass cartridge having a by-pass formed therein, saidby-pass cartridge being mounted within said outer housing, a septumlocated at a front end of said by-pass cartridge, a first plungerlocated at a rear end of said by-pass cartridge, a second plungerlocated intermediate said septum and said first plunger, said secondplunger being located rearwardly of said by-pass, a syringe socket at afront end of said outer housing, said syringe socket including apiercing member extending inwardly towards said septum, a firstcompartment having a pharmaceutical substance therein being definedbetween said septum and said second plunger, a second compartment havinga diluent therein being defined between said first and second plungers;securing a syringe to said syringe socket, said syringe having a syringeplunger mounted therein, said syringe plunger having a fluid passagewaytherein, a hydrophobic membrane covering said fluid passageway, saidhydrophobic membrane permitting the passage of gas therethrough;securing a plunger rod to said first plunger at the rear end of saidby-pass cartridge; advancing said first plunger to thereby cause saidsecond plunger to move to said by-pass and permit said diluent in saidsecond compartment to mix with said substance in said first compartmentto thereby form a mixture; exerting a continued pressure on said plungerrod to cause air to advance from said first compartment to said syringeand through said hydrophobic membrane; exerting a continuing pressure onsaid plunger rod such that said mixture from said first compartmentpasses through said piercing member into said syringe; and using aplunger rod to move said syringe plunger to retransfer said mixture intosaid first compartment of said by-pass cartridge. Through said piercingmember to thereby subject said mixture to a shearing action.
 2. Themethod of claim 1 wherein said pharmaceutical substance is in the formof microspheres.
 3. The method of claim 1 wherein said piercing memberhas an internal diameter of less than fifty thou.
 4. The method of claim3 wherein said piercing member has an internal diameter of less than 42thou.
 5. The method of claim 4 wherein said piercing member has aninternal diameter of less than 21 thou.